The TDP-43 protein plays a role in a broad suite of neurodegenerative disorders including Frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis, and potentially, Alzheimer's disease. TDP-43 is a multifunctional protein with many known cellular roles. So, while the importance of TDP-43 in neurodegeneration is established, the mechanisms of TDP-43 toxicity are unclear. We have discovered a new role for TDP-43 in regulating small-RNA based gene silencing, which is critical to block expression of retrotransposons. Retrotransposons are virus-like sequences that are encoded in our genomes and are capable of replicating and inserting at new chromosomal positions. The toxic potential of transposons in the germline is established. So our discovery provides a plausible hypothesis for toxic effects of TDP-43 in neurons. Our preliminary studies provide strong evidence that TDP-43 normally helps to silence transposons and that this function is disrupted both in FTLD patients and a Drosophila disease model. Our proposed experiments will use genetic manipulations in Drosophila to test three key specific hypotheses: 1) that TDP-43 pathology disrupts argonaute-2 mediated silencing; 2) that TDP-43 pathology activates retrotransposons in Drosophila brain; 3) that Retrotransposon activation contributes to neurodegeneration